What is the best approach to treat anemia in a patient with chronic kidney disease (CKD)?

Treatment of CKD Anemia

Initiate iron supplementation first when transferrin saturation (TSAT) ≤30% and ferritin ≤500 ng/mL, then add erythropoiesis-stimulating agents (ESAs) only if hemoglobin remains below 10 g/dL after iron repletion, targeting a hemoglobin range of 10-12 g/dL and never exceeding 12 g/dL. 1, 2

Step 1: Initial Evaluation

Before starting any anemia treatment, obtain the following laboratory tests 1, 2:

• Complete blood count with absolute reticulocyte count
• Serum ferritin level
• Transferrin saturation (TSAT)
• Serum vitamin B12 and folate levels

Exclude and correct other reversible causes of anemia including 3:

• Folate deficiency
• Vitamin B12 deficiency
• Hypothyroidism
• Hemoglobinopathies (thalassemia)
• Active bleeding
• Infection and inflammation

Step 2: Iron Supplementation (First-Line Therapy)

For Non-Dialysis CKD Patients

Initiate iron when TSAT ≤30% AND ferritin ≤500 ng/mL 1, 2:

• Intravenous iron is preferred for faster repletion 1
• Oral iron trial (1-3 months) is acceptable if patient preference or IV access issues 1, 2
• Oral iron absorption is limited when ferritin exceeds 200 ng/mL or TSAT exceeds 20% 3

For Hemodialysis Patients

Use proactive intravenous iron strategy 1, 2:

• IV iron is the preferred route 2
• Target TSAT ≤30% and ferritin ≤500 ng/mL 2
• Administer 25-100 mg IV iron weekly for 10 weeks, or 31.25-125 mg iron gluconate weekly for 8 weeks 3
• Monitor TSAT and ferritin 2-7 days after last dose (7 days for doses of 100-125 mg) 3

Available IV Iron Preparations

The following formulations are available 3:

• Iron dextran (INFeD, Dexferrum)
• Sodium ferric gluconate complex (Ferrlecit)
• Iron sucrose (Venofer)

Monitor patients for 60 minutes after IV iron infusion with resuscitative facilities available 2

Step 3: ESA Therapy (Second-Line, After Iron Repletion)

When to Initiate ESAs

Start ESA therapy only when ALL of the following criteria are met 3, 1, 2:

• Iron stores have been corrected (TSAT >30%, ferritin >500 ng/mL)
• Other reversible causes of anemia have been treated
• Hemoglobin remains sustained below 10 g/dL despite iron repletion
• Do NOT initiate if hemoglobin ≥10 g/dL 2

Critical Contraindications to ESA Use

Do not use ESAs in patients with 1, 4:

• Active malignancy
• History of stroke
• Uncontrolled hypertension
• Pure red cell aplasia (PRCA) from prior ESA exposure
• Serious allergic reactions to ESAs

Hemoglobin Target Range

Target hemoglobin: 10-12 g/dL (never exceed 12 g/dL) 3, 1, 2, 4:

• Targeting hemoglobin >11 g/dL increases risk of death, myocardial infarction, stroke, and thromboembolism 3, 4
• Multiple trials (CHOIR, CREATE, TREAT) demonstrated increased cardiovascular events and mortality with higher targets 5
• No trial has identified a hemoglobin target, ESA dose, or dosing strategy that eliminates these risks 4

ESA Dosing Regimens

For Hemodialysis Patients 3, 4:

• Initial dose: 50-100 Units/kg three times weekly (adults)
• Intravenous route is recommended for hemodialysis patients 3
• Individualize maintenance dose based on response

For Non-Dialysis CKD Patients 4:

• Initial dose: 50-100 Units/kg three times weekly
• Subcutaneous administration is more effective than IV for short-acting ESAs 1

For Pediatric Patients 4:

• Initial dose: 50 Units/kg three times weekly

Available ESA Options

Epoetin alfa (short-acting) 3, 1, 4:

• Epogen (Amgen) or Procrit (Ortho Biotech)
• Dosed three times weekly

Darbepoetin alfa (long-acting) 1, 6:

• Longer half-life allows less frequent dosing
• Comparable efficacy to epoetin

Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors (HIF-PHIs) 3, 1, 7, 8:

• Oral agents that upregulate endogenous erythropoietin production
• May improve iron utilization and be effective in ESA-hyporesponsive patients 8
• Particularly convenient for non-dialysis CKD patients 1
• Long-term safety data still emerging 7

Step 4: Managing ESA Hyporesponsiveness

Define hyporesponsiveness as failure of hemoglobin to increase from baseline after one month of appropriate weight-based ESA dosing 1

Investigate the following causes 1, 8:

• Absolute or functional iron deficiency (most common)
• Infection or inflammation (increases hepcidin, blocks iron utilization)
• Severe hyperparathyroidism
• Inadequate dialysis
• Malnutrition
• Concomitant medications
• Occult blood loss

For inflammatory ESA hyporesponse, consider HIF-PHIs as they reduce hepcidin and improve iron availability regardless of inflammation status 8

Step 5: Monitoring Strategy

Iron Parameters

Check iron studies every 3 months, or more frequently when 3, 2:

• Initiating therapy
• Clinical status changes
• Iron stores may become depleted

Hemoglobin Monitoring

Monitor hemoglobin at least every 3 months in CKD patients with eGFR <30 mL/min/1.73 m² 9

Safety Monitoring During ESA Therapy

Monitor for 3, 4:

• Blood pressure elevation (control hypertension before and during ESA therapy)
• Seizure activity (ESAs increase seizure risk in CKD patients)
• Thrombotic events
• Pure red cell aplasia (severe anemia with low reticulocyte count)

Step 6: Transfusion Therapy

Avoid red blood cell transfusions when possible to minimize 1:

• Allosensitization (problematic for transplant candidates)
• Transfusion-related risks
• Iron overload

Consider transfusion only when 1:

• ESA therapy is ineffective or contraindicated
• Immediate correction of anemia is required for hemodynamic stability

Common Pitfalls to Avoid

Do not start ESAs before correcting iron deficiency 3, 1, 2:

• ESAs increase iron utilization and will unmask or worsen iron deficiency
• This leads to ESA hyporesponsiveness and wasted therapy

Do not target hemoglobin >12 g/dL 3, 1, 4:

• The FDA boxed warning emphasizes increased mortality, cardiovascular events, and stroke with higher targets
• Use the lowest ESA dose sufficient to reduce transfusion need

Do not ignore functional iron deficiency 9, 2:

• Low TSAT despite high ferritin indicates inflammation-mediated iron sequestration via hepcidin
• May require IV iron despite elevated ferritin

Do not use benzyl alcohol-containing multi-dose vials in neonates, infants, pregnant women, or lactating women 4:

• Use only single-dose vials in these populations

For surgical patients receiving ESAs, provide DVT prophylaxis due to increased thrombotic risk 4